U.S. Pat. No. 3,652,589 discloses a class of analgesic cycloalkanol-substituted phenol esters having a basic amine group in the cycloalkyl ring. The compound (1RS, 2RS)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)cyclohexanol, commonly known as tramadol, is specifically disclosed therein. A series of articles pertaining to the pharmacology, toxicology and clinical studies of tramadol are found in Arzneim. Forsch. (Drug Res.), 28(I), 114 (1978). Driessen et al., Arch. Pharmacol., 341, R104 (1990) disclose that tramadol produces its analgesic effect through a mechanism that is neither fully opioid-like nor non-opioid-like. The Abstracts of the VIth World Congress on Pain, Apr. 1-6 (1990) disclose that tramadol hydrochloride is an orally active pure opioid agonist analgesic. However, clinical experience indicates that tramadol lacks many of the typical side effects of opioid agonists, e.g., respiratory depression (W. Vogel et al., Arzneim. Forsch. (Drug Res.), 28(I), 183 (1978)), constipation (I. Arend et al., Arzneim. Forsch. (Drug Res.), 28(I), 199 (1978 )), tolerance (L. Flohe et al., Arzneim. Forsch. (Drug Res.), 28(I), 213 (1978)), and abuse liability (T. Yanagita, Arzneim. Forsch. (Drug Res.), 28(I), 158 (1978)). When given at a dose of 50 mg by rapid I.V. injection, tramadol may, however, produce certain side effects unique to tramadol including hot flashes and sweating. Another disadvantage to the use of tramadol is that it is an immediate acting drug and thus must be taken a number of times over a 24 hour period to sustain analgesia. Despite these disadvantages, tramadol's combination of non-opioid and opioid activity makes tramadol a very unique drug. Tramadol is currently being marketed by Grunenthal GMBH in Germany as an analgesic.
Opioids have for many years been used as analgesics to treat severe pain. They, however, produce undesirable side effects and as a result cannot be given repeatedly or at high doses. The side effect problems are well documented in the literature. See, J. Jaffe in "Goodman and Gilman's, The Pharmacological Basis of Therapeutics", 8th edition; Gilman et al.; Peragamon Press, New York, 1990; Chapter 22; pages 522-573 wherein it is disclosed that morphine and its congeners, e.g., codeine, hydrocodone and oxycodone, are opioid agonist analgesics that exhibit side effects such as respiratory depression, constipation, tolerance and abuse liability.
In the search for other opiate compounds and in the quest to define the metabolism of opiate compounds, derivatives of opioids have been prepared and examined to assess the pharmacological activity of the derivatives. Flick et al., Arzneim, Forsch., 28, 107 (1978), disclose that the only desmethyl tramadol that exhibits analgesia is the O-desmethyl tramadol, and the reference also discloses that the O-desmethyl tramadol is analgesically more effective than tramadol. B. Klentey et al., Arzneim. Forsch., 7, 594 (1957) disclose that the N-oxides of dihydromorphinone, morphinone and dihydrohydroxycodeinone do not exhibit any analgesic effect. The reference does disclose that the N-oxides exhibit anti-tussive effects and do effect a dose-dependent increase in intestinal tonicity and peristalsis; however, they do not affect the normal blood pressure. Furthermore, the reference discloses that the duration of respiratory depression effected by codeine at a concentration of 10 mg/kg and by dihydrooxycodeinone-N-oxide at concentrations of 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg is nearly the same.
The prior art, therefore, does not disclose or suggest an N-oxide of a tramadol material or that the N-oxide of a tramadol material would exhibit an analgesic effect or would exhibit a pharmacological effect having a longer duration, e.g., of analgesia, than its corresponding non-N-oxide, e.g., tramadol.